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1
Bouillon, Alexandre. "Les acides et esters halogenopyridinyl et pyrimidinyl boroniques : synthèse et étude physicochimique." Caen, 2003. http://www.theses.fr/2003CAEN4064.
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Spencer, Keith. "Parallel synthesis of C-nucleosides." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.325958.
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Xu, Kuiying. "Pyrrolo[2,3-d]pyrimidine, Pyrazolo[3,4-d]pyrimidine and Triazolo[4,5-d]pyrimidine nucleosides and oligonucleotides: Synthesis, physical properties and base-pairing = Pyrrolo[2,3-d]pyrimidin, Pyrazolo[3,4-d]pyrimidin und Triazolo[4,5-d]pyrimidin nucleoside und oligonucleotide: Synthese, physikalische Eigenschaften und Basenpaarung /." Osnabrück, 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000254557.
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Ibrahim, Mohamed M. "Pyrimidine Metabolism in Rhizobium: Physiological Aspects of Pyrimidine Salvage." Thesis, University of North Texas, 1989. https://digital.library.unt.edu/ark:/67531/metadc330907/.
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The objective of this research was to study the pyrimidine salvage pathways of Rhizobium. Three approaches were used to define the pyrimidine salvage pathways operative in two species of Rhizobium, R. meliloti and R. leguminosarum . The first approach was to ascertain the pyrimidine bases and nucleosides that could satisfy the pyrimidine requirement of pyrimidine auxotrophs. Uracil, cytosine, uridine or cytidine all satisfied the absolute pyrimidine requirement. The second approach was to select for mutants resistant to 5-fluoropyrimidine analogues which block known steps in the interconversion of the pyrimidine bases and nucleosides. Mutants resistant to 5-fluorouracil lacked the enzyme uracil phosphoribosyltransferase (upp ) and could no longer use uracil to satisfy their pyrimidine requirement. Mutants resistant to 5-fluorocytosine, while remaining sensitive to 5- fluorouracil, lacked cytosine deaminase (cod) and thus could no longer use cytosine to satisfy their pyrimidine auxotrophy. The third approach used a reversed phase HPLC column to identify the products that accumulated when cytidine, uridine or cytosine was incubated with cell extracts of wild type and analogue resistant mutants of Rhizobium. When cytidine was incubated with cell extracts of Rhizobium wild type, uridine, uracil and cytosine were produced. This Indicated that Rhizobium had an active cytidine deaminase (cdd) and either uridine phosphorylase or uridine hydrolase. By dialyzing the extract and reincubating it with cytidine, uridine and uracil still appeared. This proved that it was a hydrolase ( nuh ) rather than a phosphorylase that degraded the nucleoside. Thus, Rhizobium was found to contain an active cytidine deaminase and cytosine deaminase with no uridine phosphorylase present. The nucleoside hydrolase was active with cytidine, uridine and to a far lesser extent with purines, adenosine and inosine. When high concentrations of cytidine were added to mutants devoid of hydrolase, cytosine was produced from cytidine - 5-monophosphate by the sequential action of uridine ( cytidine ) kinase and nucleoside monophosphate glycosylase. Both ft meliloti and ft leguminosarum had identical salvage pathways.
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Beck, Debrah A. (Debrah Ann). "Pyrimidine Salvage Enzymes in Microorganisms: Labyrinths of Enzymatic Diversity." Thesis, University of North Texas, 1995. https://digital.library.unt.edu/ark:/67531/metadc278204/.
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Pyrimidine salvage pathways are essential to all cells. They provide a balance of RNA synthesis with the biosynthetic pathway in pyrimidine prototrophs and supply all the pyrimidine requirements in auxotrophs. While the pyrimidine biosynthetic pathway is found in almost all organisms and is nearly identical throughout nature, the salvage pathway often differs from species to species, with aspects of salvage seen in every organism. Thus significant taxonomic value may be ascribed to the salvage pathway. The pyrimidine salvage pathways were studied in 55 microorganisms. Nine different salvage motifs, grouped I-IX, were identified in this study based on the presence of different combinations of the following enzymes: cytidine deaminase (Cdd), cytosine deaminase (Cod), uridine phosphorylase (Udp), uracil phosphoribosyltransferase (Upp), uridine hydrolase (Udh), nucleoside hydrolase (Nuh), uridine/cytidine kinase (Udk), 5'-nucleotidase and CMP kinase (Cmk).
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Roush, Wendy A. "Pyrimidine Genes in Pseudomonas Species." Thesis, University of North Texas, 2003. https://digital.library.unt.edu/ark:/67531/metadc4395/.
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This thesis is a comparative study of gene arrangements in Pseudomonas species, and is organized into three major sections. The first section compares gene arrangements for different pathways in Pseudomonas aeruginosa PAO1 to determine if the gene arrangements are similar to previous studies. It also serves as a reference for pyrimidine gene arrangements in P. aeruginosa. The second part compares the physical, and genetic maps of P. aeruginosa PAO1 with the genome sequence. The final section compares pyrimidine gene arrangements in three species of Pseudomonas. Pyrimidine biosynthesis and salvage genes will be aligned for P. aeruginosa PAO1, P. putida KT2440, and P. syringae DC3000. The whole study will gives insight into gene patterns in Pseudomonas, with a focus on pyrimidine genes.
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Hughes, Lee E. (Lee Everette). "Pyrimidine Metabolism in Streptomyces griseus." Thesis, University of North Texas, 1994. https://digital.library.unt.edu/ark:/67531/metadc278710/.
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Salvage of pyrimidine nucleosides and bases by S. griseus and the regulation of aspartate transcarbamoylase (ATCase) were studied. The velocity-substrate curve for S. griseus ATCase was hyperbolic for both aspartate and carbamoylphosphate. The enzyme activity was diminished in the presence of ATP, CTP, or UTP. The synthesis of ATCase was repressed in cells grown in the presence of exogenous uracil. The specific activity of cells grown with uracil was 43 percent of that for cells grown in minimal medium only. Maximal ATCase and dihydroorotase activities were found in the same column fraction after size-exclusion chromatography, suggesting that both activities could reside in the same polypeptide. The pyrimidine salvage enzymes cytosine deaminase and uridine phosphorylase were identified in S. griseus using HPLC reversed-phase chromatography.
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Asfour, Hani. "Regulation of pyrimidine biosynthesis and virulence factor production in wild type, Pyr- and Crc- mutants in Pseudomonas aeruginosa." Thesis, University of North Texas, 2006. https://digital.library.unt.edu/ark:/67531/metadc5297/.
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Previous research in our laboratory established that pyrB, pyrC or pyrD knock-out mutants in Pseudomonas aeruginosa required pyrimidines for growth. Each mutant was also discovered to be defective in the production of virulence factors. Moreover, the addition of exogenous uracil did not restore the mutant to wild type virulence levels. In an earlier study using non-pathogenic P. putida, mutants blocked in one of the first three enzymes of the pyrimidine pathway produced no pyoverdine pigment while mutants blocked in the fourth, fifth or sixth steps produced copious quantities of pigment, just like wild type P. putida. The present study explored the correlation between pyrimidine auxotrophy and pigment production in P. aeruginosa. Since the pigment pyoverdine is a siderophore it may also be considered a virulence factor. Other virulence factors tested included casein protease, elastase, hemolysin, swimming, swarming and twitching motilities, and iron binding capacity. In all cases, these virulence factors were significantly decreased in the pyrB, pyrC or pyrD mutants and even in the presence of uracil did not attain wild type levels. In order to complete this comprehensive study, pyrimidine mutants blocked in the fifth (pyrE) and sixth (pyrF) steps of the biosynthetic pathway were examined in P. aeruginosa. A third mutant, crc, was also studied because of its location within 80 base pairs of the pyrE gene on the P. aeruginosa chromosome and because of its importance for carbon source utilization. Production of the virulence factors listed above showed a significant decrease in the three mutant strains used in this study when compared with the wild type. This finding may be exploited for novel chemotherapy strategies for ameliorating P. aeruginosa infections in cystic fibrosis patients.
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Hughes, Lee E. (Lee Everette). "Pyrimidine Biosynthesis in the Genus Streptomyces : Characterization of Aspartate Transcarbamoylase and Its Interaction with Other Pyrimidine Enzymes." Thesis, University of North Texas, 1998. https://digital.library.unt.edu/ark:/67531/metadc278797/.
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Patel, Monal V. "The regulatory roles of PyrR and Crc in pyrimidine metabolism in Pseudomonas aeruginosa." Thesis, University of North Texas, 2001. https://digital.library.unt.edu/ark:/67531/metadc2875/.
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The regulatory gene for pyrimidine biosynthesis has been identified and designated pyrR. The pyrR gene product was purified to homogeneity and found to have a monomeric molecular mass of 19 kDa. The pyrR gene is located directly upstream of the pyrBC' genes in the pyrRBC' operon. Insertional mutagenesis of pyrR led to a 50- 70% decrease in the expression of pyrBC', pyrD, pyrE and pyrF while pyrC was unchanged. This suggests that PyrR is a positive activator. The upstream regions of the pyrD, pyrE and pyrF genes contain a common conserved 9 bp sequence to which the purified PyrR protein is proposed to bind. This consensus sequence is absent in pyrC but is present, as an imperfect inverted repeat separated by 11 bp, within the promoter region of pyrR. Gel retardation assays using upstream DNA fragments proved PyrR binds to the DNA of pyrD, pyrE, pyrF as well as pyrR. This suggests that expression of pyrR is autoregulated; moreover, a stable stem-loop structure was determined in the pyrR promoter region such that the SD sequence and the translation start codon for pyrR is sequestered. β-galactosidase activity from transcriptional pyrR::lacZ fusion assays, showed a two-fold in increase when expressed in a pyrR- strain compared to the isogenic pyrR+ strain. Thus, pyrR is negatively regulated while the other pyr genes (except pyrC) are positively activated by PyrR. That no regulation was seen for pyrC is in keeping with the recent discovery of a second functional pyrC that is not regulated in P. aeruginosa. Gel filtration chromatography shows the PyrR protein exists in a dynamic equilibrium, and it is proposed that PyrR functions as a monomer in activating pyrD, pyrE and pyrF and as a dimeric repressor for pyrR by binding to the inverted repeat. A related study discovered that the catabolite repression control (Crc) protein was indirectly involved in pyr gene regulation, and shown to negatively regulate expression of PyrR at the posttranscriptional level.
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Chang, Mingren. "Characterization of Pyrimidine Biosynthesis in Pseudomonas putida Using Mutant and Wild Type Strains." Thesis, University of North Texas, 1991. https://digital.library.unt.edu/ark:/67531/metadc500647/.
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The biosynthesis of pyrimidines in Pseudomonas putida was investigated. In this study, pyrimidine requiring mutants were isolated by conventional mutagenesis and enrichment. The strains required exogenously supplied pyrimidines for growth and were found by enzyme assays to be deficient for the product of the pyrB gene encoding the enzyme aspartate transcarbamoylase. None of the intermediates of the pathway could supply the auxotrophic requirement of the strain; only preformed pyrimidines, metabolized via salvage pathways could suffice. Pyrimidine limitation in the mutant caused a slight but significant fifty per cent increase in expression of all the de novo biosynthetic enzymes. Pyrimidine starvation's effect on nucleotide pool levels was examined in the mutant and caused a marked swelling of the purine nucleotide pools.
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Brichta, Dayna Michelle. "Construction of a Pseudomonas aeruginosa Dihydroorotase Mutant and the Discovery of a Novel Link between Pyrimidine Biosynthetic Intermediates and the Ability to Produce Virulence Factors." Thesis, University of North Texas, 2003. https://digital.library.unt.edu/ark:/67531/metadc4344/.
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The ability to synthesize pyrimidine nucleotides is essential for most organisms. Pyrimidines are required for RNA and DNA synthesis, as well as cell wall synthesis and the metabolism of certain carbohydrates. Recent findings, however, indicate that the pyrimidine biosynthetic pathway and its intermediates maybe more important for bacterial metabolism than originally thought. Maksimova et al., 1994, reported that a P. putida M, pyrimidine auxotroph in the third step of the pathway, dihydroorotase (DHOase), failed to produce the siderophore pyoverdin. We created a PAO1 DHOase pyrimidine auxotroph to determine if this was also true for P. aeruginosa. Creation of this mutant was a two-step process, as P. aeruginosa has two pyrC genes (pyrC and pyrC2), both of which encode active DHOase enzymes. The pyrC gene was inactivated by gene replacement with a truncated form of the gene. Next, the pyrC2 gene was insertionally inactivated with the aacC1 gentamicin resistance gene, isolated from pCGMW. The resulting pyrimidine auxotroph produced significantly less pyoverdin than did the wild type. In addition, the mutant produced 40% less of the phenazine antibiotic, pyocyanin, than did the wild type. As both of these compounds have been reported to be vital to the virulence response of P. aeruginosa, we decided to test the ability of the DHOase mutant strain to produce other virulence factors as well. Here we report that a block in the conversion of carbamoyl aspartate (CAA) to dihydroorotate significantly impairs the ability of P. aeruginosa to affect virulence. We believe that the accumulation of CAA in the cell is the root cause of this observed defect. This research demonstrates a potential role for pyrimidine intermediates in the virulence response of P. aeruginosa and may lead to novel targets for chemotherapy against P. aeruginosa infections.
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Kumar, Alan P. "Structure-Function Studies on Aspartate Transcarbamoylase and Regulation of Pyrimidine Biosynthesis by a Positive Activator Protein, PyrR in Pseudomonas putida." Thesis, University of North Texas, 2003. https://digital.library.unt.edu/ark:/67531/metadc4362/.
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The regulation of pyrimidine biosynthesis was studied in Pseudomonas putida. The biosynthetic and salvage pathways provide pyrimidine nucleotides for RNA, DNA, cell membrane and cell wall biosynthesis. Pyrimidine metabolism is intensely studied because many of its enzymes are targets for chemotheraphy. Four aspects of pyrimidine regulation are described in this dissertation. Chapter I compares the salvage pathways of Escherichia coli and P. putida. Surprisingly, P. putida lacks several salvage enzymes including nucleoside kinases, uridine phosphorylase and cytidine deaminase. Without a functional nucleoside kinase, it was impossible to feed exogenous uridine to P. putida. To obviate this problem, uridine kinase was transferred to P. putida from E. coli and shown to function in this heterologous host. Chapter II details the enzymology of Pseudomonas aspartate transcarbamoylase (ATCase), its allosteric regulation and how it is assembled. The E. coli ATCase is a dodecamer of two different polypeptides, encoded by pyrBI. Six regulatory (PyrI) and six catalytic (PyrB) polypeptides assemble from two preformed trimers (B3) and three preformed regulatory dimers (I2) in the conserved 2B3:3I2 molecular structure. The Pseudomonas ATCase also assembles from two different polypeptides encoded by pyrBC'. However, a PyrB polypeptide combines with a PyrC. polypeptide to form a PyrB:PyrC. protomer; six of these assemble into a dodecamer of structure 2B3:3C'2. pyrC' encodes an inactive dihydroorotase with pyrB and pyrC' overlapping by 4 bp. Chapter III explores how catabolite repression affects pyrimidine metabolism. The global catabolite repression control protein, Crc, has been shown to affect pyrimidine metabolism in a number of ways. This includes orotate transport for use as pyrimidine, carbon and nitrogen sources. Orotate is important because it interacts with PyrR in repressing the pyr genes. Chapter IV describes PyrR, the positive activator of the pyrimidine pathway. As with other positive activator proteins, when pyrimidine nucleotides are depleted, PyrR binds to DNA thereby enhancing expression of pyrD, pyrE and pyrF genes. When pyrimidine nucleotides are in excess, the PyrR apoprotein binds to orotate, its co-repressor, to shut down all the pyrimidine genes. Like many positive activators, PyrR is subject to autoregulation and has catalytic activity for uracil phosphoribosyltransferase inducible by orotate.
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Clain, Jérôme. "Inhibiteurs de la biosynthèse des pyrimidines chez Plasmodium falciparum : mode d'action et mécanisme de résistance." Paris 5, 1998. http://www.theses.fr/1998PA05P100.
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Black, Duncan Arthur. "Aspects of purine and pyrimidine metabolism." Doctoral thesis, University of Cape Town, 1989. http://hdl.handle.net/11427/26590.
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In Chapter 1 a review of the literature concerning aspects of erythrocyte membrane transport and metabolism, and purine and pyrimidine metabolism is presented. The effects of pH, pO₂ and inorganic phosphate (Pi) on the uptake and metabolism of hypoxanthine by erythrocytes has been studied in Chapter 2. Uptake of hypoxanthine and accumulation of inosine 5'-monophosphate (IMP) were markedly increased at acid pH, high external phosphate concentrations, and low pO₂. Release of accumulated IMP as hypoxanthine occurred at alkaline pH values and low external phosphate concentrations. Conditions favouring IMP accumulation gave rise, in the absence of hypoxanthine, to a corresponding increase in 5'-phosphoribosyl-1-pyrophosphate (PRPP). Intracellular phosphate concentrations were markedly pH dependent and a model is presented whereby hypoxanthine uptake and release are controlled by intracellular concentrations of inorganic phosphate and 2,3- bisphosphoglycerate (2,3-DPG). These allosteric effectors influence, in opposing ways, two enzymes governing IMP accumulation, namely PRPP synthetase and 5'-nucleotidase. These metabolic properties suggest that the erythrocyte could play a role in the removal of hypoxanthine from anoxic tissue. In Chapter 3 the kinetics and mechanism of transport of orotate across the human erythrocyte membrane and the effect of pH and inorganic phosphate on its metabolism (in the erythrocyte) have been studied. It has been shown that orotate enters erythrocytes with non-saturable kinetics and with a capacity of 190 μmoles/1 packed cells/min at a concentration of 4-6 mmolar. The presence of competition for transport by a number of anions and the lack of competition by uridine is indicative of transport by a general anion transporter, with the ability for concentrative uptake in the absence of other external anions being compatible with transport via a ping-pong mechanism. Inhibition of transport by the specific band 3 inhibitors DIDS and CHCA confirm that transport is via the band 3 anion transporter. This explains the lack of significant uptake of orotate by most differentiated tissues which lack the intact band 3 protein. However, the demonstration of band 3 in rat hepatocytes (Cheng and Levy, 1980) provides a mechanism for the orotate transport which has been observed in liver (Handschumacher and Coleridge, 1979). Changes in pH and inorganic phosphate (Pi) concentrations have been shown to have marked effects on the relative quantities of metabolic products produced by the erythrocyte from orotate. There was an increase in orotate metabolised with increasing Pi, an effect augmented by lowering the pH, and most easily explained by the allosteric activation of PRPP synthetase by Pi. The increase in UTP levels with decreasing pH may be the consequence of both increased PRPP availability for the formation of uridine nucleotide from orotate, and decreased conversion of UMP to uridine by pyrimidine 5'-nucleotidase, which is known to be inhibited by phosphate. The accumulation of UDP sugars is optimal at a phosphate concentration of 10 mmolar, which is unexplained but would be compatible with an inhibitory effect of Pi on CTP synthetase. A PRPP wasting cycle at alkaline pH values is proposed to explain the apparent paradox where no PRPP was observed to accumulate in erythrocytes (Chapter 2) at pH values of 7.6 and above in the presence of 10 mmolar phosphate and no added hypoxanthine, yet the metabolism of orotate, which is a PRPP utilising reaction, at alkaline pH values was readily demonstrable here. This (apparent paradox) can be resolved if one assumes that even in the absence of added hypoxanthine and demonstrable intracellular IMP there are sufficient quantities of hypoxanthine and/or IMP to maintain a PRPP wasting cycle at alkaline pH values. The cycle is interrupted at acidic pH values as phosphate levels rise and inhibit 5'-nucleotidase, an effect augmented by the decreasing levels of 2,3-DPG which accompany decreasing pH. This wasting cycle has recently been confirmed by P. Berman (unpublished). The kinetics of orotate uptake by erythrocytes and its eventual release as uridine provides a role for the erythrocyte in the transport and distribution of pyrimidines to peripheral tissues. A model is proposed and involves the de novo production of orotate in the liver. In the next step erythrocytes take up the orotate secreted by the liver into the circulation, convert it into an intermediate buffer store of uridine nucleotides, whose distribution is a function of pH and phosphate concentration, and eventually release it as uridine, which is a readily available form of pyrimidine for utilisation by peripheral nucleated cells. The enhancement of uptake of labelled orotate into nucleic acids of cultured cells is demonstrated here. The degradative half of the cycle proposes that uracil and palanine are the predominant degradative forms of pyrimidines produced by peripheral cells, and their ultimate metabolic fate is complete catabolism in the liver to CO₂ and water. In the final chapter the possible role of the human erythrocyte in the prevention of reperfusion injury has been investigated. The development of a model of renal ischaemia in the rat is described. The ability of human erythrocytes, "primed" by preincubating in acid medium of high Pi concentration and low pO₂, to take up hypoxanthine in a concentrative manner when perfused through ischaemic rat kidney is demonstrated. Attempts to demonstrate improved survival and renal function in rats with "primed" human erythrocytes prior to reperfusion were, however, unsuccessful. It is further demonstrated that "unprimed" human erythrocytes, resident in ischaemic rat kidney for 3 hours, take up hypoxanthine and convert it to IMP. that erythrocytes could play a physiological prevention of reperfusion injury.
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Scott, Allelia Worrall. "Pyrimidine Nucleoside Metabolism in Pseudomonads and Enteric Bacteria." Thesis, University of North Texas, 1991. https://digital.library.unt.edu/ark:/67531/metadc500941/.
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Metabolic differences in the strategies used for pyrimidine base and nucleoside salvage were studied in the pseudomonads and enteric bacteria. Fluoro--analogs were used to select mutant strains of E. coli, S. typhimurium, P. putida, and P. aeruginosa blocked in one or more of the uracil and uridine salvage enzymes. HPLC analysis of cell-free extracts from wild-type and mutant strains examined the effectiveness of the selections. Evidence was found for cytidine kinase in Pseudomonas and for an activity that converted uracil compounds to cytosine compounds. Using media supplemented with 150 μg of orotic acid per ml, P. putida SOC 1, a Pyr, upp mutant which utilizes orotic acid as a pyrimidine source was isolated for the first time in any study.
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Lee, Yick-Shun. "Pyrimidine Metabolism in Bacteria: Physiological Properties of Nucleoside Hydrolase and Uridine Kinase." Thesis, University of North Texas, 1991. https://digital.library.unt.edu/ark:/67531/metadc798309/.
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Ralli, Pooja. "Impaired virulence factor production in a dihydroorotate dehydrogenase mutant (pyrD) of Pseudomonas aeruginosa." Thesis, University of North Texas, 2005. https://digital.library.unt.edu/ark:/67531/metadc4940/.
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Previous research in our laboratory showed that when knockout mutations were created in the pyrB and pyrC genes of the pyrimidine pathway in Pseudomonas aeruginosa, not only were the resultant mutants auxotrophic for pyrimidines but they were also impaired in virulence factor production. Such a correlation had not been previously reported for P. aeruginosa, a ubiquitous opportunistic pathogen in humans. In an earlier study it was reported that mutants blocked in one of the first three enzymes of the pyrimidine pathway in the non-pathogenic strain P. putida M produced no pyoverdin pigment while mutants blocked in the later steps produced copious amounts of pigment, just like the wild type. This study probed for the same connection between pyrimidine auxotrophy and pigment production applied in P. aeruginosa. To that end a knockout mutation was created in pyrD, the fourth step in the pyrimidine pathway which encodes dihydroorotate dehydrogenase. The resulting mutant required pyrimidines for growth but produced wild type pigment levels. Since the pigment pyoverdin is a siderophore it may also be considered a virulence factor, other virulence factors were quantified in the mutant. These included casein protease, hemolysin, elastase, swimming, swarming and twitching motility, and iron binding capacity. In all cases these virulence factors were significantly decreased in the mutant. Even supplementing with uracil did not attain wild type levels. Starvation of the pyrimidine mutant for uracil caused increased specific activity of the pyrimidine enzymes, suggesting that regulation of the pyrimidine pathway occurred at the level of transcription. This effect has also been reported for P. oleovorans. The present research consolidates the idea that pyrimidine auxotrophs cause decreased pathogenicity in P. aeruginosa. Such a finding may open the search for chemotherapy targets in cystic fibrosis and burn victims where P. aeruginosa is an infecting agent.
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Nicolle, Edwige. "Nouvelles thiazolidino [3,2-a] pyrimidines : synthèse, étude structurale et pharmacologique." Université Joseph Fourier (Grenoble), 1990. http://www.theses.fr/1990GRE18007.
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Sullivan, Shannon M. "Synthesis of 2,4-disubstituted pyrimidine derivatives as potential 5-HT7 receptor antagonist." unrestricted, 2008. http://etd.gsu.edu/theses/available/etd-05052008-153400/.
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Thesis (M.S.)--Georgia State University, 2008.Title from file title page. Lucjan Strekowski, committee chair; A.L. Baumstark, Gabor Patonay, Doyle Barrow , committee members. Electronic text (68 p. : ill.) : digital, PDF file. Description based on contents viewed June 23, 2008. Includes bibliographical references (p. 42-430.
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Niazy, Abdurahman. "Investigating the Ability of Pseudomonas aeruginosa pyrE Mutants to Grow and Produce Virulence Factors." Thesis, University of North Texas, 2014. https://digital.library.unt.edu/ark:/67531/metadc700016/.
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Pseudomonas aeruginosa are medically important bacteria that are notorious for causing nosocomial infections. To gain more knowledge into understanding how this organism operates, it was decided to explore the pyrimidine biosynthetic pathway. Pyrimidine synthesis, being one half of the DNA structure, makes it a very important pathway to the organism’s survivability. With previous studies being done on various genes in the pathway, pyrE has not been studied to the fullest extent. To study the function of pyrE, a site directed mutagenesis was done to completely knock out pyrE, which encodes the protein orotate phosphoribosyl transferase that is responsible for converting orotate into orotate monophosphate (OMP). A mutation in this step leads to accumulation and secretion of orotate into the medium. Analyzing virulence factors produced by the mutant and comparing to the wild type, some intriguing features of the mutant were discovered. One of the findings was the over expression of virulence factors pyoverdin and pyocyanin. Pyocyanin over expression, based on the results of this study, is due to the accumulation of orotate while over production of pyoverdin is due to the accumulation of dihydroorotate. The other virulence factors studied were motility assays, exoproducts, and growth analysis. All virulence factor production was reduced significantly in the mutant compared to the wild type. The casein protease assay showed absolutely no production of proteases in the mutant. The conclusion is that orotate accumulation leads to a significant reduction in virulence factor production in Pseudomonas aeruginosa. In addition to that, it was found that excess orotate in the wild type led to a decrease in quorum sensing regulated products.
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Meixner, Jeffery Andrew. "Investigation of Pyrimidine Salvage Pathways to Categorize Indigenous Soil Bacteria of Agricultural and Medical Importance and Analysis of the Pyrimidine Biosynthetic Pathway's Enzyme Properties for Correlating Cell Morphology to Function in All Phases of Growth." Thesis, University of North Texas, 2003. https://digital.library.unt.edu/ark:/67531/metadc4194/.
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This dissertation comprises three parts and is presented in two chapters. Chapter 1 concerns Arthrobacter, a bacterium with an intriguing growth cycle. Whereas most bacteria exist as either a rod or coccus, this bacterium shares the rod/coccus lifestyle. It therefore seemed important to examine the growth regulatory pathways from the rod and coccus. The committed step, that catalyzed by aspartate transcarbamoylase (ATCase), in the pyrimidine biosynthetic pathway was chosen. The ATCase in Arthrobacter is like the well known Pseudomonas enzyme except that it has an active dihydroorotase (DHOase) associated.
Included in Chapter 1 is the description of a microorganism, Burkholderia cepacia, whose ATCase has characteristics that are at once reminiscent of bacteria, mammals, and fungi. It differs in size or aggregation based on environmental conditions. In addition, it has an active DHOase associated with the ATCase, like Arthrobacter. B. cepacia is important both medically and for bioremediation. Since B. cepacia is resistant to most antibiotics, its unique ATCase is a prime target for inhibition.
Whereas the first chapter deals with the de novo pathway to making pyrimidines, which is found mainly in the lag and log phase, Chapter 2 addresses the salvage pathway, which comes more into play during the stationary phase. This section focuses on the isolation, identification, and grouping of a number of natural soil bacteria from various soil locations. These organisms are important agriculturally, medically, and industrially. Addition of these soil isolates to poor soils has been found to improve the soil. In a previous study by D.A. Beck, the salvage schemes for a number of laboratory strains of microorganisms were determined. Nine separate classes of salvage were designated by determining the salvage enzymes present. In this study emphasis has been placed on soil bacteria, which had not previously been analyzed. A number of species of soil bacteria were identified using the MIDI. The salvage enzymes were then determined for these organisms and a comparison of these isolates to the previous study was performed in order to group the new organisms into 19 salvage schemes, that is 10 more than in the previous study.
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Griffin, Roger J. "Novel biological roles for pyrimidines." Thesis, Aston University, 1986. http://publications.aston.ac.uk/12540/.
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The development of classical and lipophilic inhibitors of dihydrofolate reductase (DHFR) as antitumour agents is reviewed and the advantages and problems associated with each class are discussed. The antitumour activity, pharmacokinetics and metabolism of m-azido-pyrimethamine (MZP), a novel lipophilic inhibitor, are considered and compared with metoprine, the prototype lipophilic antifolate. Evidence for a folate-independent target for lipophilic DHFR inhibitors is presented. Synthetic studies centred on three principal objectives. Firstly a series of structural analogues of MZP were prepared encompassing alkoxy, chloro and alkylamino substituents and evaluated, as the ethanesulphonate salts, for activity against mammalian DHFR. Inhibitory constant (KI) determinations were conducted by a Zone B analysis, the corresponding 4'-azido isomer of MZP proving more potent than the parent compound. Secondly, to facilitate metabolism and stability studies on MZP, a range of possible reference compounds were synthesised and characterised. Finally, a series of diaminopyrimidine derivatives were synthesised embracing structural features incompatible with DHFR inhibitory activity, in order that such compounds may serve as biochemical probes for the unidentified folate-independent target for lipophilic diaminopyrimidines discussed previously. Inactivity against DHFR was achieved via introduction of an ionic or basic group into a normally hydrophobic region of the molecule and compounds were screened against a mammalian DHFR and thymidylate synthase to confirm the abolition of activity. Several derivatives surprisingly proved potent inhibitors of DHFR exhibiting KI values comparable to that of methotrexate. Analogues were screened for antitumour activity in vitro and in vivo against murine leukaemia cell lines in order to identify potential lead compounds. Several derivatives virtually inactive against DHFR exhibited a disparate cytotoxicity and further biochemical studies are warranted. The nobreak hitherto unreported debenzylation of 2,4-diamino-5-(N-alkyl-benzylaminophenyl) pyrimidines was discovered during the course of the synthetic studies, treatment of these compounds with nitrous acid affording the corresponding benzotriazoles.
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Lee, Jeong-Hwan. "Synthesis of pyrrolo[2,3-d]pyrimidines and pyrazino[2,3-d]pyrimidines and their biological activities." Thesis, University of Strathclyde, 2010. http://oleg.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=14350.
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Eguae, Samuel Iyamu. "Pyrimidine nucleotide metabolism in Rhizobium meliloti: purification of aspartate transcarbamoylase from a pyrimidine auxotroph." Thesis, University of North Texas, 1990. https://digital.library.unt.edu/ark:/67531/metadc332674/.
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Rhizobium aspartate transcarbamoylase (ATCase; EC 2.1.3.2) was previously believed to be similar to the Pseudomonas ATCase which has been studied extensively. To facilitate the study of the Rhizobium ATCase a pyrimidine-requiring mutant of R. meliloti was isolated and used in the purification of the enzyme.
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Collins, James P. "Prebiotic Synthesis of Pyrimidine Nucleosides." Thesis, Georgia Institute of Technology, 2005. http://hdl.handle.net/1853/14095.
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The problem of forming a glycosidic bond between ribose and the free nucleoside bases to produce beta-nucleosides under plausible prebiotic conditions is commonly referred to in origin of life research as The Nucleoside Problem. The lack of a general solution to this problem currently represents one of the largest stumbling blocks to the RNA world hypothesis and many other theories regarding the origin of life. Over thirty years ago the purine nucleosides were successfully synthesized by drying the fully-formed bases and ribose together in the presence of divalent metal ion salts. However, glycosidic bond formation by the pyrimidine bases has never been achieved under similar reaction conditions. This thesis describes the first plausible prebiotic synthesis of a pyrimidine nucleoside, demonstrated with the pyrimidine base analogue 2-pyrimidinone. Information provided by nucleoside-formation reaction involving 2-pyrimidinone and related pyrimidine bases should provide valuable insights into the possible mechanism by which glycosidic bond formation was accomplished on the prebiotic Earth.
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Hastewell, J. G. "Pyrimidine transport in rat small intestine." Thesis, University of York, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.373286.
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Lottermoser, Ursula Maria. "Untersuchungen an substituierten Pyrimidinen und verwandten Verbindungen." [S.l. : s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=972318992.
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Langlet, Abraham. "Nitration of oxo-pyrimidines and oxo-imidazoles /." Stockholm, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-601.
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Parks, Emma Louise. "Polyfunctionalised pyrimidines and pyrazines from perhalogenated precursors." Thesis, Durham University, 2008. http://etheses.dur.ac.uk/2551/.
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Chapter 1 introduces the modem pharmaceutical industry in terms of the drug discovery process leading into a discussion of the relevance of heterocyclic compounds with particular focus on the synthesis of multifunctional pyrimidines and pyrazines. An introduction into organofluorine chemistry is included followed by a review of the literature on 5-chloro-trifluoropyrimidine, tetrafluoropyrimidine and tetrafluoropyrazine. Chapter 2 describes a study of the reactivity of 5-chlorotrifluoropyrimidine with mono- and difunctional-nucleophiles. This research demonstrates the former are not selective and in the latter the 5-position chlorine atom is inert to nucleophilic aromatic substitution and cross-coupling methodologies. Chapter 3 explores the reactivity of tetrafluoropyrimidine with nitrogen, sulphur and oxygen containing nucleophiles and describes the development of a methodology for the synthesis of multisubstituted pyrimidines by establishing the regioselectivities of such processes. Chapter 4 investigates the reactivity of tetrafluoropyrimidine with difunctional nucleophiles. This study indicated it was not possible to synthesise [5,6]-ring fused systems and that in some cases dimers were formed owing to the 5-position fluorine atom being inactive substitution. Chapter 5 discusses the use of tetrafluoropyrazine in the syntheses of [5,6] ring-fused systems. The reactivity of the system towards MiV-dinucleophiles and C,0-dinucleophiles was investigated. Further functionalisations by nucleophilic aromatic substitution of the remaining fluorine atoms with nitrogen and oxygen nucleophiles are also discussed. Chapter 6 contains the experimental data for Chapters 2 to 5.
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Prieur, Vanessa. "Pyrrolo[2,3-d]pyrimidines : conception, synthèse, fonctionnalisation." Thesis, Orléans, 2015. http://www.theses.fr/2015ORLE2072/document.
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Les pyrrolo[2,3-d]pyrimidines, également connues sous le nom de 7-déazapurines, sont une classe importante d’hétérocycliques aromatiques, de par leurs potentiels biologiques (antitumoral, antiinflammatoire, antibactérien, etc.). C’est pourquoi ce squelette a été une source d’intérêt pour les chimistes organiciens. Outre leurs atouts biologiques, ces molécules présentent également de remarquables propriétés physico-chimiques (fluorescence UV), ce qui permet de nouvelles applications en électronique. Bien que ces dernières années, un bon nombre de recherche ont été mises en oeuvre en vue de synthétiser ces molécules, il n’existe encore que peu de méthodes générales pour obtenir des pyrrolo[2,3-d]pyrimidines hautement substituées. Le but de ces travaux de thèse est de développer différentes stratégies régiosélectives et chimiosélectives de synthèse pour accéder à des pyrrolo[2,3-d]pyrimidines diversement substituées et ce, en un minimum d’étapes. Dans un premier temps, il a été synthétisé une famille de 7-méthylpyrrolo[2,3-d]pyrimidines 4,5,6 triarylées notamment via l’utilisation de deux réactions de Suzuki-Miyaura. Pour faire suite, nous avons envisagé la préparation d’une série de pyrrolopyrimidines 2,4,6-triarylées où le motif aromatique de la position 2 est introduit suivant les conditions de Liebeskind-Srogl. Enfin la préparation de pyrrolo[2,3-d]pyrimidines 4-aminées à partir d’alkynylpyrimidines a été mise au point et divers composés de cette famille ont été élaborésThe pyrrolo [2,3-d]pyrimidines, also known as 7-deazapurines, are an important class of aromatic heterocycles by their biological potencial (antitumor, anti-inflammatory, antibacterial, etc.). Therefore, this skeleton is a source of interest for the organic chemists. A part of the biological activity, these compounds present also outstanding physicochemical properties (UV-fluorescence); enabling new applications in electronics. The last few years, a great number of researches have been put in execution with a view to synthesizing these molecules, where still few general methods exist to obtain pyrrolo [2,3-d] pyrimidines highly substituted. The aim of these works of thesis is to develop different regioselective and chemoselective synthetic strategies to accede to pyrrolo [2,3-d]pyrimidines diversely substituted and furthemore in a reduced number of steps. First has been synthesized a family of 4,5,6-triarylated-7-methylpyrrolo[2,3-d]pyrimidines including the use of two Suzuki-Miyaura's reactions. Also we contemplated the preparation of a series of 2,4,6-triarylated pyrrolopyrimidines where the aryl group at the position 2 has been introduced under Liebeskind-Srogl reaction conditions. Finally the preparation of 4-aminated pyrrolo [2,3-d] pyrimidines from alkynylpyrimidines has been fine-tuned and diverse derivative compounds have been synthesized
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Swetnam, S. P. "N.M.R. studies of the protonation of pyrimidines." Thesis, Keele University, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.372826.
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Barnes, Samuel. "Synthesis of 2, 4-distributed pyrimidines of possible biological interest." unrestricted, 2008. http://etd.gsu.edu/theses/available/etd-05012008-164917/.
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Thesis (M.S.)--Georgia State University, 2008.Title from file title page. Lucjan Strekowski, committee chair; A.L. Baumstark, Jerry Smith, committee members. Electronic text (83 p. : ill.) : digital, PDF file. Description based on contents viewed August 8, 2008. Includes bibliographical references (p. 44-46).
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Ratelle, Guillaume. "Incorporation spécifique d'une pyrimidine oxydée dans l'ADN cellulaire." Sherbrooke : Université de Sherbrooke, 2001.
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Turan, Y. "Pyrimidine primary and secondary metabolism in plants." Thesis, Swansea University, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.639271.
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In this study, the biosynthesis of albizziine has been elucidated, and a direct precursor relationship shown to exist between uracil and albizziine. This was confirmed by the demonstration that [2-14C]uracil specifically labels C-5 of albizziine. It is concluded that the biosynthetic sequence involves the hydroxylation of uracil to isobarbituric acid, then amination to 5-aminouracil, followed by hydrogenation and ring-opening, to yield albizziine. 2,3-Diaminopropanoic acid was shown to be formed from albizziine by the action of β-ureidopropionase. Thus, the formation of albizziine and 2,3-diaminopropanoic acid represents a further aspect of the interfacing of pyrimidine primary and secondary metabolism through uracil. Lathyrine was shown to be catabolyzed in Lathyrus tingitanus to yield the non-protein amino acid 4-hydroxyhomoarginine, and it was thus confirmed that 4-hydroxyhomoarginine is a catabolite rather than a precursor of lathyrine. 2-Amino-4-carboxypyrimidine, the immediate precursor of the lathyrine ring-system, was shown to be synthesized enzymically from uracil. The relative amount of exogenously supplied uracil diverted into production of the isomeric pyrimidinyl amino acids willardiine and isowillardiine in Pisum sativum, and also that diverted into the production of the pyrimidine amino acid lathyrine in Lathyrus tingitanus was determined. Uracil was shown to have a pronounced inhibitory effect on the germination and growth of Phaseolus aureus and Glycine max. As these plants do not produce pyrimidine-derived secondary products, this observation is consistent with the view that production of such compounds is a detoxification mechanism for bioactive pyrimidines.
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Sen, Gupta Soma. "Purine and pyrimidine transport in Candida spp." Thesis, University of Cambridge, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.296640.
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Hill, Matthew D. (Matthew Dennis). "Direct synthesis of pyridine and pyrimidine derivatives." Thesis, Massachusetts Institute of Technology, 2008. http://hdl.handle.net/1721.1/43776.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2008.Vita.
Includes bibliographical references.
I. Synthesis of Substituted Pyridine Derivatives via the Ruthenium-Catalyzed Cycloisomerization of 3-Azadienynes. The two-step conversion of various N-vinyl and N-aryl amides to the corresponding substituted pyridines and quinolines, respectively, is described. The process involves the direct conversion of amides, including sensitive N-vinyl amides, to the corresponding trimethylsilyl alkynyl imines followed by a ruthenium-catalyzed protodesilylation and cycloisomerization. A wide range of new alkynyl imines are prepared and readily converted to the corresponding azaheterocycles. II. Single-Step Synthesis of Pyrimidine Derivatives. The single-step conversion of various N-vinyl and N-aryl amides to the corresponding pyrimidine and quinazoline derivatives, respectively, is described. The process involves amide activation with 2-chloropyridine and trifluoromethanesulfonic anhydride followed by nitrile addition into the reactive intermediate and cycloisomerization. In situ nitrile generation from primary amides allows for their use as nitrile surrogates. The use of this chemistry with sensitive N-vinyl amides and epimerizable substrates in addition to a wide range of functional groups is noteworthy. III. Direct Synthesis of Pyridine Derivatives. The single-step conversion of various N-vinyl and N-aryl amides to the corresponding pyridine and quinoline derivatives, respectively, is described. The process involves amide activation with trifluoromethanesulfonic anhydride in the presence of 2-chloropyridine followed by t-nucleophile addition to the activated intermediate and annulation. Compatibility of this chemistry with sensitive N-vinyl amides, epimerizable substrates, and a variety of functional groups is noteworthy.
by Matthew D. Hill.
Ph.D.
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Ali, Juma Ahmed Mohmed. "Pyrimidine salvage and metabolism in kinetoplastid parasites." Thesis, University of Glasgow, 2013. http://theses.gla.ac.uk/4664/.
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Pyrimidine uptake has previously been investigated in Trypanosoma brucei procyclics and partly investigated in promastigotes of Leishmania major; however, no such study has been performed using bloodstream forms of Trypanosoma or promastigotes of Leishmania. Here we report a comprehensive study of pyrimidine salvage and metabolism in bloodstream forms of Trypanosoma and promastigotes of Leishmania species. In T. b. brucei bloodstream forms, the uptake of 3H-uracil and 3H-tymidine each appeared to be mediated by a single transporter, designated TbU3 and TbT1, respectively. The procyclic uracil transporter,TbU1, has a high affinity for uracil, with a Km value of 0.46 ± 0.09 μM and Vmax of 0.65 ± 0.008 pmol (107cell)-1 s-1. These values were similar for TbU3 (Km = 0.54 ± 0.11 µM; Vmax = 0.14 ± 0.03), but the main differences between TbU1 and TbU3 are their sensitivity to uridine and 4-thiouracil. Thymidine uptake is detectable at 10 μM over a period from 5 to 30 minutes. This uptake was not inhibited by uracil which indicates that TbT1 is a novel thymidine transporter. The uptake of other pyrimidines, including uridine and 2’-deoxyuridine, by BSF are investigated here but these substrates were also transported by TbU3, and no additional pyrimidine transport activities were found. In L. mexicana and L. major, the uptake of 3H-uracil and 3H-uridine was mediated by separate transporters, designated as follows; for uracil uptake LmexU1, LmajU1; and for uridine uptake LmexNT1, LmajNT1 and LmajNT2, respectively. LmexU1 is a uracil transporter with high affinity to uridine and 2’deoxyuridine, and the LmexNT1 is a nucleoside transporter with broad specificity for purine and pyrimidine nucleosides. L. major uracil transporter (LmajU1) has already been reported by others; and here we report that there are also two distinct uridine transporters expressed in L. major. LmajNT1 is a high affinity uridine transporter which is also inhibited by uracil, inosine and adenine; LmajNT2 is low affinity uridine transporter, with very poor affinity for uracil, inosine and adenine. However, both transporters are inhibited by 2’-deoxyuridine, thymidine and adenosine. Several fluorinated pyrimidine analogues were assessed against kinetoplastid cells, the most effective compounds, which displayed EC50 values at micromolar level, are 5-FU, 5F-2’dUrd, 5-FOA (only against T. brucei BSF) and 5F-Urd (only against L. major). We induced resistance to 5-FU, 5-F2’dUrd and 5-FOA by in vitro exposure of Tbb-BSF and promastigotes of L. mexicana and L. major. The resistance was performed by stepwise increase concentration of the drugs. For T. b. brucei BSF, the resistance factors of clonal lines were 131, 825, and 83-fold, respectively. For L. mexicana and L. major, the resistance factor for 5-FU were 147 and 17-fold, and for 5F-2’dUrd were >3500 and 381-fold, respectively. We also measured 3H–pyrimidine uptake in these cell lines; the resistant bloodstream form strains showed no changes in pyrimidine uptake, with one exception, which is a 76% reduction in 5-FU uptake. In contrast, each resistant strain of Leishmania spp had lost its natural pyrimidine transporter. For example, Leishmania cells resistant to 5-FU had lost uracil transport activity, and cells that were resistant to 5F-2’dUrd had lost uridine transport activity. In addition, we identified kinetoplastid genes that appeared to be associated with resistance to fluorinated pyrimidines. Based on these findings, metabolomic analysis of fluorinated pyrimidines in T. b. brucei resistant cell lines was performed in comparison with parental wild-type; for Leishmania species we only investigated the metabolism of fluorinated pyrimidine in wild type cells, as the fluorinated analogues were simply not taken up in the resistant clones. The metabolomic analysis data showed that, in T. b. brucei, 5-fluorouracil and 5-fluoro orotate are incorporated into a large number of metabolites, but likely act through incorporation into RNA. 5F-2’dUrd and 5F-2’dCtd are not incorporated into nucleic acids but act as prodrugs by inhibiting thymidylate synthase after conversion to 5F-dUMP. Cells treated with 5-fluoro-2’deoxyuridine showed an increase of dUMP, which suggest a block in thymidylate synthase or possibly thymidylate kinase. We also present the most complete model of pyrimidine salvage in T. brucei to date, supported by genome-wide profiling of the predicted pyrimidine biosynthesis and conversion enzymes. The effect of fluorinated pyrimidine analogues in the two Leishmania species was almost identical. Each of the tested drugs (5-FU, 5F-2’dUrd and 5F-Urd) produced a limited number of fluorinated metabolites, and their common mode of action was inhibition in thymidylate synthase by 5F-dUMP and thymidine kinase by 5F-2’dUrd. Interestingly, we found that the cause of L. mexicana resistance to 5F-Urd was due to the absence of the 5F-2’dUrd metabolite, as a result of the rapid conversion of 5F-2’dUrd to 5F-dUMP; also we suggest that, in L. mexicana, but not in L. major the high affinity salvage of thymidine is sufficient to provide the cells with thymidine deoxynucleotides. It has been found that pyrimidine salvage is not an essential function for Leishmania cells in vitro conditions. However, it is not known whether either, pyrimidine salvage or biosynthesis, or both of these systems are essential to the trypanosomes in vitro and in vivo study. As T. b. brucei bloodstream forms grew unimpeded in vitro in the complete absence of pyrimidines, uptake is clearly not essential. Disruption of the pyrimidine biosynthesis pathway by deletion of the OMPDCase/OPRTase gene resulted in pyrimidine auxotrophic trypanosomes that were unable to grow in the absence of added pyrimidines. The phenotype was rescued by addition of uracil, and to a lesser extent by some pyrimidine nucleosides. Pyrimidine starvation led rapidly to DNA fragmentation. Adaptations to low pyrimidine availability included upregulation of uracil transport capacity and of uridine phosphorylase expression. However, pyrimidine auxotrophic T. brucei were able to establish a high parasitemia in mice. We therefore conclude that pyrimidine salvage was not an essential function for bloodstream T. b. brucei. However, trypanosomes lacking de novo pyrimidine biosynthesis are completely dependent on an extracellular pyrimidine source, strongly preferring uracil, and display reduced infectivity and strongly increased sensitivity to fluorinated pyrimidines. As T. brucei are able to salvage sufficient pyrimidines from the host environment, the pyrimidine biosynthesis pathway is not a viable drug target, although any interruption of pyrimidine supply was lethal.
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PERIGNON, JEAN-LOUIS. "Metabolisme des pyrimidines dans les cellules lymphoides humaines." Paris 6, 1987. http://www.theses.fr/1987PA066799.
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Afin d'estimer le role du metabolisme intermediaire des pyrimidines dans la reponse immunitaire, la fonction immunitaire de deux malades ayant un deficit enzymatique hereditaire portant sur la voie de synthese de novo des pyrimidines (oroticurie) est etudie. Le metabolisme intermediaire des nucleosides pyrimidiques dans des lymphocytes et lymphoblastes humains fait l'objet d'une deuxieme etude
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Stewart, John E. B. (John Edward Bakos). "Characterization of Aspartate Transcarbamoylase in the Archaebacterium Methanococcus Jannaschii." Thesis, University of North Texas, 1996. https://digital.library.unt.edu/ark:/67531/metadc935724/.
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Asparate transcarbamoylase catalyzes the first committed step in the de novo synthesis of pyrmidine nucleotides UMP, UDP, UTP, and CTP. The archetype enzyme found in Escherichia coli (310 kDa) exhibits sigmodial substrate binding kinetics with positive control by ATP and negative control with CTP and UTP. The ATCase characterized in this study is from the extreme thermophilic Archaebacterium, Methanococcus jannaschii. The enzyme was very stable at elevated temperatures and possessed activity from 20 degrees Celsius to 90 degrees Celsius. M. Jannaschii ATCase retained 75% of its activity after incubation at 100 degrees Celsius for a period of 90 minutes. No sigmodial allosteric response to substrate for the enzyme was observed. Velocity substrate plots gave Michaelis-Menten (hyperbolic) kinetics. The Km for aspartate was 7 mM at 30 degrees Celsius and the KM for carbamoylphosphate was .125 mM. The enzyme from M. jannaschii had a broad pH response with an optimum above pH 9. Kinetic measurements were significantly affected by changes in pH and temperature. The enzyme catalyzed reaction had an energy of activation of 10,300 calories per mole. ATCase from M. jannaschii was partially purified. The enzyme was shown to have a molecular weight of 110,000 Da., with a subunit molecular weight of 37,000 Da. The enzyme was thus a trimer composed of three identical subunits. The enzyme did not possess any regulatory response and no evidence for a regulatory polypeptide was found, DNA from M. jannaschii did hybridize to probes corresponding to genes for both the catalytic and regulatory subunits from E. coli. Analysis of DNA sequences for the M. jannaschii ATCase genes showed that the gene for the catalytic subunits shares significant homology with the pyrB genes from E. coli, and maximum homology amongst known ATCase genes to pyrB from Bacillus. An unlinked gene homologous to E. coli pyrl encoding the regulatory subunit was identified, though its expression and true function remain uncharacterized.
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Vickrey, John F. (John Fredrick) 1959. "Isolation and Characterization of the Operon Containing Aspartate Transcarbamoylase and Dihydroorotase from Pseudomonas aeruginosa." Thesis, University of North Texas, 1993. https://digital.library.unt.edu/ark:/67531/metadc278859/.
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The Pseudomonas aeruginosa ATCase was cloned and sequenced to determine the correct size, subunit composition and architecture of this pivotal enzyme in pyrimidine biosynthesis. During the course of this work, it was determined that the ATCase of Pseudomonas was not 360,000 Da but rather present in a complex of 484,000 Da consisting of two different polypeptides (36,000 Da and 44,000 Da) with an architecture similar to that of E. coli ATCase, 2(C3):3(r2). However, there was no regulatory polypeptide found in the Pseudomonas ATCase.
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AsFour, Hani. "Effector Response of the Aspartate Transcarbamoylase From Wild Type Pseudomonas Putida and a Mutant with 11 Amino Acids Deleted at the N-terminus of PyrB." Thesis, University of North Texas, 2002. https://digital.library.unt.edu/ark:/67531/metadc3163/.
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Like its enteric counterpart, aspartate transcarbamoylase (ATCase) from Pseudomonas putida is a dodecamer of two different polypeptides. Unlike the enterics, the Pseudomonas ATCase lacks regulatory polypeptides but employs instead inactive dihydroorotases for an active dodecamer. Previous work showed that PyrB contains not only the active site but also the effector binding sites for ATP, UTP and CTP at its N-terminus. In this work, 11 amino acids were deleted from the N-terminus of PyrB and the ATCase with the truncated protein was expressed in E. coli pyrB- and purified. The wild type enzyme was similarly treated. Velocity-substrate plots without effectors gave Michaelis-Menten kinetics in all cases. Deleting 11 amino acids did not affect dodecameric assembly but altered effector responses. When carbamoylphosphate was varied, the mutant enzyme was inhibited by UTP while the wild type enzyme was activated 2-fold. When the aspartate was varied, CTP had no effect on the mutant enzyme but strongly inhibited the wild type enzyme.
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Entezampour, Mohammad. "Quantitation of Endogenous Nucleotide Pools in Pseudomonas aeruginosa." Thesis, University of North Texas, 1988. https://digital.library.unt.edu/ark:/67531/metadc500491/.
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Nucleotide pools were extracted and quantified from Pyr^+ and Pyr^- strains of P. aerucjinosa. Strains were grown in succinate minimal medium with and without pyrimidines, and nucleotides were extracted using trichloracetic acid (TCA; 6% w/v). The pyrimidine requirement was satisfied by uracil, uridine, cytosine or cytidine. Pyr^- mutants were starved for pyrimidines for two hours before nucleotide levels were measured. This starvation depleted the nucleotide pools which were restored to wild type levels by the addition of pyrimidines to the medium. When the pyrimidine analogue, 6-azauracil, known to inhibit OMP decarboxylase, was added to cultures of the wild type strain, the uridine and cytidine nucleotides were depleted to near zero. Thus, the nucleotide pool levels of Pseudomonas strains can be manipulated.
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Borssum, Waalkes Marjan van. "Lipophilic derivatives of 5-fluoro-2'-deoxyuridine as liposomal anticancer agents." [S.l. : [Groningen : s.n.] ; University Library Groningen] [Host], 1992. http://irs.ub.rug.nl/ppn/292987617.
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Simkovsky, Nadja Melitta. "Synthesis of some potential IKK inhibitors based around a pyrimidine scaffold." Thesis, University of Liverpool, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.367619.
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Brom, Jacques. "Squelettes pyrimidohétérocycliques dérivés d'amino- et d'hydrazino- uraciles." Mulhouse, 1991. http://www.theses.fr/1991MULH0205.
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Les 6-amino-, 6-hydrazino- et 6-(azavinyl) pyrimidinediones riches en électrons réagissent par leur carbone 5 avec différents électrophiles (l’O-tosylisonitrosomalodinitrile (OTMD), le tétracyanoéthylène (TCNE), l'acétylènedicarboxylate de diméthyle (DMAD), et le diméthylacétal du diméthylformamide (DMFDMA) pour conduire après cyclisation à toute une série d'hétérocycles polycycliques. La 6-amino-1,3-diméthylpyrimidine-2,4(1H, 3H)-dione fournit ainsi, avec l'OTMD, une lumazine précurseur de pyrimido [5,4-g] ptéridines, et avec le TCNE, une pyrido [2,3-d] pyrimidine. Une isomérisation du squelette carboné est mise en évidence dans le cas de la réaction entre la 6-hydrazino-1,3-diméthylpyrimidine-2,4(1H, 3H) dione et le TCNE. Des réactions analogues sur carbone sont également observées dans les séries naphtaléniques et anthracéniques
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Simon, Gaëlle. "Analogues et dérivés des méridianines : Synthèse et Étude structure-activité biologique." Brest, 2004. http://www.theses.fr/2004BRES2011.
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Le milieu marin est une source de molécules bioactives originales. Les méridianines, indoles substitués en position 3 par un reste pyrimidine, font partie de ces molécules découvertes récemment qui présentent une activité inhibitrice des kinases cycline-dépendantes. Afin de compléter les premiers tests biologiques sur ces indolopyrimidines, nous rapportons dans un premier temps la synthèse d'analogues NH des méridianines par deux voies : un couplage de Suzuki entre des acides indolylboroniques et une 2-amino-4-chloropyrimidine et, la formation d'un cycle 2-aminopyrimidine par condensation de la guanidine sur des ènaminones obtenues par réaction du DMF-DMA sur des 3-acétylindoles. Nous avons, dans un deuxième temps, préparé selon cette même synthèse linéaire des dérivés N-alkylés des méridianines, la formation de l'ènaminone nécessitant, cette fois, la présence de pyrrolidine. Enfin, les synthèses de divers dérivés ont été réalisées en remplaçant l'indole par le cycle 1,2,3,9-tetrahydro-4H-carbazol-4-one ou par variations autour du cycle 2-aminopyrimidine. Une partie de ces molécules a ensuite été testée, dans le cadre de la recherche contre le cancer, sur des kinases cycline-dépendantes (GSK-3 et CDK1) et sur des lignées cellulaires (RAJI, DAUDI, K562). Une série de tests a également été réalisée sur la fixation des larves de balanes afin de préciser les propriétés antifouling de ces nouvelles moléculesThe marine environment constitues a very promising source for novel and bioactive molecules, and meridianins have been identified among those recently discovered. These indoles with a 2-aminopyrimidine at C-3 can inhibit cyclin-dependent kinases. In order to conduct additionnal biological tests about these 3-(2-aminopyrimidine)indoles, we first synthesised NH meridianin-analogues through two routes: (i) a Miyaura-Suzuki coupling of indol-3-ylboronic acids to 2-amino-4-chloropyrimidine, and (ii) the formation of a 2-amino-pyrimidine by guanidine condensation with enaminones issued from the reaction of N,N-dimethylformamide dimethylacetal (DMF-DMA) with 3-acetylindoles. Then, in a second stage we prepared N-alkyled derivatives of meridianins by applying the same linear synthesis, using pyrrolidine for the formation of enaminones. At last, various derivatives were prepared by replacing the indole with the 1,2,3,9-tetrahydro-4H-carbazol-4-one cycle or using various pyrimidines. Some of these molecules were finally tested against cyclin-dependent kinases (GSK-3 and CDK1) and cell lines (RAJI, DAUDI and K562) as part of cancer-related researches. Other tests about the fixation of barnacle larvae were also performed to investigate the antifouling properties of these new molecules
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Mondon, K. J. "Enzyme inactivation by pyrimidine and purine free radicals." Thesis, Brunel University, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.332433.
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Ladebeck, Oliver. "Studies of DNA repair by Cyclobutane pyrimidine dimers." Thesis, Cardiff University, 2010. http://orca.cf.ac.uk/54956/.
Full textAbstract:
Cyclobutane pyrimidine dimers (CPDs) are the major photo products that can occur in DNA after UV-light exposure. Detrimental effects of CPDs for organisms can be prevented by the DNA repair enzyme DNA photolyase. This protein repairs CPDs by a light induced (300–500 nm) electron transfer involving a non-covalently bound cofactor, FAD. The key role of FAD in the catalytic DNA repair can be investigated by replacing FAD in the enzyme with FAD analogues and compare the activity of wild-type enzyme to the mutant enzyme. As a part of this study, a stable expression system of photolyase was created and the enzyme was purified in concentrations in the uM range. The FAD analogue roseoFAD was biochemically synthesised from its precursor form roseoflavin. FAD was extracted from photolyase by unfolding the enzyme using the effects of denaturing agents or changes in buffer pH values. The protein was successfully refolded in the presence of roseoFAD and its integration into the proteins active site was confirmed by UV/Vis spectroscopy. Surface plasmon resonance spectroscopy (SPR) was used to monitor DNA repair by photolyase in real-time. For this purpose photolyase was overexpressed and purified. CPDs, the substrate of photolyase, were produced by UV irradiation of poly-T oligonucleotides. SPR signals were detected for steps of the repair process such as enzyme-substrate complex formation, DNA repair and release of product. Changes in SPR signals were used to obtain the kinetics of DNA repair by measuring the on and & off rates and calculating the rate constants for substrate binding and product release. According to the data obtained the dissociation constant KD was calculated and found to be in good agreement with published values obtained by different methods.
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Fasoli, Marco Oldo. "Pyrimidine transport and salvage metabolism in pathogenic Candida." Thesis, University of Cambridge, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.315023.
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